Effectiveness of Allopurinol in Reducing Mortality: Time-Related Biases in Observational Studies

Abstract

Objective: The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies have shown important reductions in mortality with allopurinol use, with wide variations in results. We undertook this review to assess the extent of bias in these studies, particularly time-related biases such as immortal time bias.

Methods: We searched the literature to identify all observational studies describing the effect of allopurinol use versus nonuse on all-cause mortality.

Results: We identified 12 observational studies, of which 3 were affected by immortal time bias and 3 by immeasurable time bias, while the remaining 6 studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio (HR) of death associated with allopurinol of 0.71 (95% confidence interval [95% CI] 0.50-1.01), as well as in those with immeasurable time bias (pooled HR 0.62 [95% CI 0.56-0.67]). The 6 studies that avoided these biases demonstrated a null effect of allopurinol on mortality (pooled HR 0.99 [95% CI 0.87-1.11]), though the lack of an analysis based on treatment adherence may have attenuated the effect.

Conclusion: Observational studies are important to provide real-world data on medication effects. The observational studies showing significantly decreased mortality with allopurinol treatment cannot be used as evidence, however, mainly due to time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomized trial, which is currently underway and evaluates the effect of adding allopurinol to usual care (compared to no added treatment), will provide reliable evidence on mortality.